Abstract: TH-PO585
Glomerular Disease Caused by Vinyl Carbamate in A/J Inbred Mice: A Novel Model of Membranoproliferative Glomerulonephritis (MPGN)
Session Information
- Glomerular Diseases: Omics, Biomarkers, and Tools
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Gong, Athena Y., University of Michigan, Ann Arbor, Michigan, United States
- Dworkin, Lance D., The University of Toledo Medical Center, Toledo, Ohio, United States
- Gunning, William T., The University of Toledo Medical Center, Toledo, Ohio, United States
- Chen, Mengxuan, The University of Toledo Medical Center, Toledo, Ohio, United States
Background
Ethyl carbamate (EC) is a process contaminant in fermented foods and alcoholic beverages. Metabolic conversion of EC generates vinyl carbamate (VC), a carcinogenic metabolite. EC, as a Group 2A probable human carcinogen, and the more potent VC, are known to cause tumors in rodents. However, their effects on the kidney are unknown.
Methods
A/J inbred mice received a single i.p. injection of VC (60 mg/kg). Kidney injury was evaluated. A post hoc analysis was performed on a publicly available RNA-Seq transcriptome of kidneys derived from rats treated with fermented wine containing high concentrations of EC.
Results
Beginning 5 weeks post VC injection, mice showed signs of moribund state and were killed. By 12 weeks, a total of 97 of the 240 treated mice had died or were killed. Necropsies of mice revealed evident renal disease, characterized by glomerular lobularization, mesangial hypercellularity and expansion, endocapillary proliferation, and capillary wall thickening by light microscopy. Electron microscopy revealed subendothelial electron-dense deposits, formation of new basement membrane between the interposed cell and endothelium, and extensive podocyte foot process effacement. On immunofluorescent staining, abundant granular mesangial C3 staining was noted along with coarse linear capillary staining, whilst immunoglobulin staining was negative. These changes were highly reminiscent of the pathology of MPGN. In addition, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on differentially expressed genes between high EC-treated and control rats, and showed that complement and coagulation cascades are top predicted biological processes implicated. Furthermore, pathway-based data integration and visualization using Pathview demonstrated that key regulators of complement activation pathways were altered by high EC treatment. Among these, complement factor (CF) D and H, critical positive and negative regulators of the alternative pathway, respectively, were the most affected, with CFD induced by 3.49-fold and CFH repressed by 5.88-fold, underscoring a hyperactive alternative pathway.
Conclusion
VC, a metabolite of EC, induces complement fixation in glomeruli and MPGN in mice. Complement overactivation due to CFD induction and CFH repression may be an underlying pathomechanism.